Pathogenesis of psoriatic arthritis: new insights from a bone marrow perspective.

Purpose Of Review: Psoriatic arthritis is an immune-mediated disease that primarily affects the skin and joints. It falls under the umbrella term of rheumatic diseases, which describes a group of closely related yet distinct disorders with many common underlying molecular pathways. Despite the distinct clinical manifestation of each disorder, the shared therapeutic strategies attest to the commonality of cellular and molecular underpinnings.

IL-23 induces CLEC5A IL-17A neutrophils and elicit skin inflammation associated with psoriatic arthritis.

IL-23-activation of IL-17 producing T cells is involved in many rheumatic diseases. Herein, we investigate the role of IL-23 in the activation of myeloid cell subsets that contribute to skin inflammation in mice and man. IL-23 gene transfer in WT, IL-23R reporter mice and subsequent analysis with spectral cytometry show that IL-23 regulates early innate immune events by inducing the expansion of a myeloid MDL1CD11bLy6G population that dictates epidermal hyperplasia, acanthosis, and parakeratosis; hallmark pathologic features of psoriasis.

Innate immune memory in inflammatory arthritis.

The concept of immunological memory was demonstrated in antiquity when protection against re-exposure to pathogens was observed during the plague of Athens. Immunological memory has been linked with the adaptive features of T and B cells; however, in the past decade, evidence has demonstrated that innate immune cells can exhibit memory, a phenomenon called 'innate immune memory' or 'trained immunity'. Innate immune memory is currently being defined and is transforming our understanding of chronic inflammation and autoimmunity.

IL-17A and IL-17F in tissue homeostasis, inflammation and regeneration.

IL-17 signalling regulates both protective and harmful immune responses; therefore, its complete inhibition can have adverse effects. Detailed consideration and fine-tuning of IL-17-inhibition strategies is needed to selectively regulate disease outcomes.

IL-27 attenuates IL-23 mediated inflammatory arthritis.

Interleukin 27 has both pro-inflammatory and anti-inflammatory properties in autoimmunity. The anti-inflammatory effects of IL-27 are linked with inhibition of Th17 differentiation but the IL-27 effect on myeloid cells is less studied. Herein we demonstrate that IL-27 inhibits IL-23-induced inflammation associated not only with Th17 cells but also with myeloid cell infiltration in the joints and splenic myeloid populations of CD11b GR1 and CD3CD11bCD11cGR1 cells.

Autophagy pathways in autoimmune diseases.

Autophagy comprises a growing range of cellular pathways, which occupy central roles in response to energy deprivation, organelle turnover and proteostasis. Over the years, autophagy has been increasingly linked to governing several aspects of immunity, including host defence against various pathogens, unconventional secretion of cytokines and antigen presentation. While canonical autophagy-mediated antigen processing in thymic epithelial cells supports the generation of a self-tolerant CD4 T cell repertoire, mounting evidence suggests that deregulated autophagy pathways contribute to or sustain autoimmune responses.

Interleukin-23 Regulates Inflammatory Osteoclastogenesis via Activation of CLEC5A(+) Osteoclast Precursors.

Objective: To investigate the role of interleukin-23 (IL-23) in pathologic bone remodeling in inflammatory arthritis.

Methods: In this study we investigated the role of IL-23 in osteoclast differentiation and activation using in vivo gene transfer techniques in wild-type and myeloid DNAX-activation protein 12-associating lectin-1 (MDL-1)-deficient mice, and by performing in vitro and in vivo osteoclastogenesis assays using spectral flow cytometry, micro-computed tomography analysis, Western blotting, and immunoprecipitation.

Results: Herein, we show that IL-23 induces the expansion of a myeloid osteoclast precursor population and supports osteoclastogenesis and bone resorption in inflammatory arthritis.

Cell-Specific and Variant-Linked Alterations in Expression of ERAP1, ERAP2, and LNPEP Aminopeptidases in Psoriasis.

ERAP1, ERAP2, and LNPEP are aminopeptidases implicated in autoimmune pathophysiology. In this study, we show that ERAP2 is upregulated and ERAP1 is downregulated in patients with psoriasis who are homozygous for autoimmune-linked variants of ERAP. We also demonstrate that aminopeptidase expression is not uniform in the skin.

Optimal Drop Height in Prepubertal Boys Is Revealed by the Performance in Squat Jump.

Drop jump (DJ) performance gain with increasing drop height is well documented in adults, but there is still no clear evidence of such gain in children. This study aimed to examine the differences in DJ performance gain in male adults and prepubescent boys by comparing drop heights tailored to each individual's performance and expressed as a percentage of their squat jump (SJ) performance. Fifteen boys (9-11 y) and 15 men (19-27 y) executed DJs from drop heights that were set at 75%, 100%, 125%, and 150% of their best performance in SJ (DJ, DJ, DJ, and DJ, respectively).

Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a posttranslational regulator of the LDL receptor (LDLR). Recent studies have proposed a role for PCSK9 in regulating immune responses. Using RNA-Seq-based variant discovery, we identified a possible psoriasis-susceptibility locus at 1p32.

Serine and arginine rich splicing factor 1 deficiency alters pathways involved in IL-17A expression and is implicated in human psoriasis.

Serine and Arginine Rich Splicing Factor 1 (SRSF1) is a splicing factor that binds to exonic enhancers and stimulates splicing and is previously implicated with autoimmunity. Herein, we investigate the role of SRSF1 in regulating innate immune functions that are pertinent in the pathogenesis of auto-inflammatory diseases. Specifically, we show that conditional deletion of SRSF1 in mature lymphocytes resulted in higher expression of il-17a and il-17 f and an expansion of IL17A CD8 T cells.

Peripheral γδ T Cells Regulate Neutrophil Expansion and Recruitment in Experimental Psoriatic Arthritis.

Objective: This study was undertaken to identify the mechanistic role of γδ T cells in the pathogenesis of experimental psoriatic arthritis (PsA).

Methods: In this study, we performed interleukin-23 (IL-23) gene transfer in wild-type (WT) and T cell receptor δ-deficient (TCRδ ) mice and conducted tissue phenotyping in the joint, skin, and nails to characterize the inflammatory infiltrate. We further performed detailed flow cytometry, immunofluorescence staining, RNA sequencing, T cell repertoire analysis, and in vitro T cell polarization assays to identify regulatory mechanisms of γδ T cells.

IL-23 reshapes kidney resident cell metabolism and promotes local kidney inflammation.

Interstitial kidney inflammation is present in various nephritides in which serum interleukin 23 (IL-23) is elevated. Here we showed that murine and human renal tubular epithelial cells (TECs) expressing the IL-23 receptor (IL-23R) responded to IL-23 by inducing intracellular calcium flux, enhancing glycolysis, and upregulating calcium/calmodulin kinase IV (CaMK4), which resulted in suppression of the expression of the arginine-degrading enzyme arginase 1 (ARG1), thus increasing in situ levels of free L-arginine. Limited availability of arginine suppressed the ability of infiltrating T cells to proliferate and produce inflammatory cytokines.

IL-23 Inhibition in Ankylosing Spondylitis: Where Did It Go Wrong?

Axial spondyloarthritis is a prevalent form of chronic arthritis which is related to psoriatic arthritis and skin psoriasis. TNF and IL-17A as well as IL-17F are key cytokines contributing to the pathobiology of this disease, as evidence by the therapeutic efficacy of inhibition of these factors. Despite the evidence that IL-23 acts as an upstream driver of Th17 cells, the T lymphocytes producing IL-17, and that IL-23 inhibition shows profound efficacy in psoriasis, blocking IL-23 failed to show any evidence of clinical efficacy in axial spondyloarthritis.

Interleukin-17 and Interleukin-23: A Narrative Review of Mechanisms of Action in Psoriasis and Associated Comorbidities.

Psoriasis is an immune-mediated inflammatory skin disease associated with numerous inflammatory comorbidities, including increased cardiovascular risk. The interleukin (IL)-23/IL-17 axis plays a central role in the immunopathogenesis of psoriasis and related comorbidities by acting to stimulate keratinocyte hyperproliferation and feed-forwarding circuits of perpetual T cell-mediated inflammation. IL-17 plays an important role in the downstream portion of the psoriatic inflammatory cascade.

Axial spondyloarthritis: new advances in diagnosis and management.

Axial spondyloarthritis (axSpA) is an inflammatory disease of the axial skeleton associated with significant pain and disability. Previously, the diagnosis of ankylosing spondylitis required advanced changes on plain radiographs of the sacroiliac joints. Classification criteria released in 2009, however, identified a subset of patients, under the age of 45, with back pain for more than three months in the absence of radiographic sacroiliitis who were classified as axSpA based on a positive magnetic resonance imaging or HLAB27 positivity and specific clinical features.

Bromodomain-containing-protein-4 and cyclin-dependent-kinase-9 inhibitors interact synergistically in vitro and combined treatment reduces post-traumatic osteoarthritis severity in mice.

Objective: Joint injury rapidly induces expression of primary response genes (PRGs), which activate a cascade of secondary genes that destroy joint tissues and initiate post-traumatic osteoarthritis (PTOA). Bromodomain-containing-protein-4 (Brd4) and cyclin-dependent-kinase-9 (CDK9) cooperatively control the rate-limiting step of PRG transactivation, including pro-inflammatory genes. This study investigated whether Brd4 and CDK9 inhibitors suppress inflammation and prevent PTOA development in vitro and in a mouse PTOA model.

A site-specific map of the human plasma glycome and its age and gender-associated alterations.

Alterations in the human glycome have been associated with cancer and autoimmunity. Thus, constructing a site-specific map of the human glycome for biomarker research and discovery has been a highly sought-after objective. However, due to analytical barriers, comprehensive site-specific glycoprofiling is difficult to perform.

Psoriatic arthritis; overcoming the challenges by creating opportunities.

Over the past few years, there have been several scientific advances related to the discovery of interleukin 23 (IL-23) and IL-17 which led to the development of new treatment options and overall improved clinical care of Psoriatic Arthritis (PsA) patients. Many of these efforts and milestones, alongside new developments, are captured in this Clinical Immunology special edition. We also take the opportunity to highlight the overall scientific progress in PsA research and also highlight some areas of concern that continue to represent barriers in the PsA arena that need to be addressed.

Psoriatic arthritis under the influence of IFNγ.

Psoriasis is a common multifactorial autoimmune disease of the skin, and in a large percentage of patients, immune responses involve nail and joint pathology, which develop psoriatic arthritis (PsA). Historically, T helper 1 (Th1)-derived-IFN-γ was abundantly detected in psoriatic skin and its correlation with development and severity of PsO, led to an early classification of psoriasis as a Th1-mediated disease. Investigations of the cellular and molecular mechanisms of PsO pathogenesis in recent years, together with impressive results of biologics against interleukin 17A (IL-17) have shifted focus on IL-17A.

Systemic lupus erythematosus favors the generation of IL-17 producing double negative T cells.

Mature double negative (DN) T cells are a population of αβ T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8 T cells.